Prostate cancer (PCa) is the leading cancer diagnosed and the second cause of cancer death in American men. Currently, therapeutic strategies for the treatment of hormone-independent metastatic PCa are very limited. The long-term goal of our competitive renewal application is to determine whether and how transforming growth factor beta (TGF?) signaling pathway can be targeted for the development of novel therapeutic approaches to inhibit PCa growth and metastasis in preclinical animal models. In our preliminary studies, we found that systemic administration of various TGF? antagonists inhibited the growth and angiogenesis of xenograft prostate tumors and metastasis of orthotopic prostate tumors. The inhibition of prostate tumor progression by TGF? antagonists was in part due to the blockade of TGF? signaling in tumor-associated stromal cells because partial blockade of TGF? signaling by the expression of a dominant-negative receptor in prostate stromal cells significantly attenuated their tumor-promoting activity. Thus, our central hypothesis in the competitive renewal application is that blockade of TGF? signaling in prostate stromal cells may be developed as a novel strategy to inhibit PCa growth and metastasis. In our specific aim 1, we will employ a tumor and stromal cell co-transplantation system to determine the role of TGF? signaling in prostate stromal cells in the regulation of tumor-stroma crosstalk and tumor progression. During the past funding cycle, we developed a novel TGF? -binding protein that can act as a pan- TGF? antagonist. We have also developed a novel androgen-receptor positive human PCa cell line that induces osteoblastic bone metastasis when inoculated intracardiacally in mice. In our specific aim 2, we will compare the efficacy of the novel pan-TGF? binding protein with that of a small TGF? type I receptor kinase inhibitor in the inhibition of growth and metastasis of the novel PCa cell line as well as other PCa cells in xenograft and orthotopic PCa models and the spontaneous PCa model of TRAMP mice. In the specific aim 3, we will test the novel hypothesis that the combination of a TGF? antagonist and a chemotherapeutic drug will produce a synergistic inhibitory effect on PCa growth and metastasis in xenograft and orthotopic PCa models. Our proposed research will reveal whether targeting TGF? signaling in tumor-associated stromal cells is feasible as a novel therapeutic approach to inhibit PCa growth and metastasis in a preclinical setting. The knowledge gained from our research may lay the foundation for clinical trials with TGF? antagonist alone or in combination with a chemotherapeutic agent for the treatment of metastatic PCa. Project Narrative Prostate cancer is a major health issue in the aging population of American men. Prostate cancer progression is associated with over-production of transforming growth factor beta (TGF?). Our preliminary studies have shown that TGF? can drive hormone-independent prostate cancer progression and metastasis. Our proposed research will determine whether systemic treatment with TGF? antagonists is of therapeutic potential for the inhibition of prostate tumor growth and bone metastasis in mouse models of prostate cancer. The knowledge gained from our research may lay the foundation for clinical trials with TGF? antagonist alone or in combination with a chemotherapeutic agent for the treatment of metastatic PCa.